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Liver Cancer 2012;1:144–158 DOI: 10.1159/000343828 Published online: November 26, 2012
© 2012 S. Karger AG, Basel 2235-1795/0014-0144$38.00/0 www.karger.com/lic
Review
Treatment of Hepatocellular Carcinoma: A Systematic Review Shibo Lin Katrin Hoffmann Peter Schemmer Department of General and Transplant Surgery, Ruprecht-Karls-University, Heidelberg, Germany
Key Words Chemotherapy · Hepatocellular carcinoma · Liver resection · Liver transplantation · Intervention therapy
Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancies, with an increasing incidence. With advances in surgical techniques and instrumentation and the development of molecular-target drugs, a number of potentially curative treatments have become available. Management of HCC patients depends on the stage of their tumor. Liver resection remains the first choice for very early-stage HCC, but it is being challenged by local ablative therapy. For early-stage HCC that meet the Milan criteria, liver transplantation still offers a better outcome; however, local ablative therapy can be a substitute when transplantation is not feasible. Local ablation is also used as a bridging therapy toward liver transplantation. HCC recurrence is the main obstacle to successful treatment, and there is currently no effective means of preventing or treating HCC recurrence. Transarterial therapy is considered suitable for intermediate-stage HCC, while sorafenib is recommended for advanced-stage HCC. This stage-based approach to therapy not only provides acceptable outcomes but also improves the quality of life of HCC patients. Because of the complexity of HCC, therapeutic approaches must be adapted according to the characteristics of each individual patient. This review discusses the current standards and trends in the treatment of HCC.
Peter Schemmer, MD
Deptment of General and Transplant Surgery, Ruprecht-Karls-University Im Neuenheimer Feld 110, Heidelberg 69120 (Germany) Tel. +49 0 6221 56 6110, E-Mail [email protected]
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Copyright © 2012 S. Karger AG, Basel
145
Liver Cancer 2012;1:144–158 DOI: 10.1159/000343828 Published online: November 26, 2012
© 2012 S. Karger AG, Basel www.karger.com/lic
Lin et al.: Systemic Review of HCC Treatment
Introduction Hepatocellular carcinoma (HCC) is the fifth most common form of cancer and the third leading cause of cancer-related death worldwide [1]. The number of cases diagnosed with HCC is expected to increase in Western countries [2]. Therapeutic approaches for the treatment of HCC can be classified into three categories: potentially curative, palliative, and symptomatic. Potentially curative treatments, including liver resection, transplantation, and local ablation, are associated with promising 5-year survival rates of up to 75% [3]. However, because of a shortage of donor livers, advanced tumor stage, or liver dysfunction, less than 20% HCC patients are eligible for such treatments [4, 5]. The majority of HCC patients are subjected to palliative or symptomatic treatment. The 3-year survival rate for palliative treatment is 10–40%, and the duration of survival for patients who receive symptomatic treatment is RFA NA ×
SR>RFA SRRFA
NA NA NA
SR = surgical resection; PTA = percutaneous thermal ablation; D = Diameter of tumor mass; OSR = overall survival rates; ORS = overall recurrence rates; RFSR = recurrence-free survival rates; DFSR = disease-free survival rates; × = no significance.
Early-stage HCC Early-stage HCC is defined according to the Milan criteria as follows: a single tumor nodule ≤5 cm in diameter or ≤3 nodules ≤3 cm in diameter [16]. Approximately 25% of all HCC patients are diagnosed with early-stage HCC [17]. According to the EASL-AASLD guidelines, early-stage HCC is an indication for liver transplantation or RFA [8]. Liver transplantation is the optimal approach, but local ablation can be a substitute when liver transplantation is not feasible. Liver resection should be considered when patients present with a solitary tumor and no portal hypertension [7]. The 4- and 5-year survival rates of patients who meet the Milan criteria and subsequently undergo liver transplantation are 85 and 70%, respectively [16, 18]. Farinati et al. reported that for patients with early-stage HCC, liver transplantation offers the best chances of survival (106 months) compared with surgical resection (52 months), RFA (62 months), percutaneous ethanol injection (PEI, 44 months), and transarterial chemoembolization (TACE, 34 months) [17]. Despite the excellent efficacy of liver transplantation in early-stage HCC treatment, a shortage of donor livers or tumor progression during the waiting period inevitably leads to patients dropping out from the waiting list. The monthly drop-out rate is approximately 4% [18, 19]. Local ablative therapies, primarily RFA, have therefore been investigated as alternative treatments for early-stage HCC that meet the Milan criteria. Although a recent meta-analysis indicated that surgical resection is superior to RFA because it results in longer overall survival, longer recurrence-free survival, and a low rate of local recurrence, the analysis was mainly based on nonrandomized controlled trials and did not include the latest 3-year survival data [20]. The conclusion should therefore be interpreted with caution. To address the efficacy of local ablative therapy in comparison with
Downloaded by: Univ. of California Santa Barbara 198.143.33.33 - 7/30/2015 2:42:37 PM
that RFA was associated with better overall survival compared with surgical resection [15]. Therefore, further research is warranted before local ablation can be recommended as firstline therapy for very early-stage HCC or as a substitute for surgical resection.
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Liver Cancer 2012;1:144–158 © 2012 S. Karger AG, Basel www.karger.com/lic
DOI: 10.1159/000343828 Published online: November 26, 2012 Lin et al.: Systemic Review of HCC Treatment
Table 3. Summary of transarterial therapies for HCC Author
Year
Doffoël [95]
2008
Llovet [93]
2002
Bruix [97]
1998
Lo [94]
GETCH [135] *P
Liver Cancer 2012;1:144–158 DOI: 10.1159/000343828 Published online: November 26, 2012
© 2012 S. Karger AG, Basel 2235-1795/0014-0144$38.00/0 www.karger.com/lic
Review
Treatment of Hepatocellular Carcinoma: A Systematic Review Shibo Lin Katrin Hoffmann Peter Schemmer Department of General and Transplant Surgery, Ruprecht-Karls-University, Heidelberg, Germany
Key Words Chemotherapy · Hepatocellular carcinoma · Liver resection · Liver transplantation · Intervention therapy
Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancies, with an increasing incidence. With advances in surgical techniques and instrumentation and the development of molecular-target drugs, a number of potentially curative treatments have become available. Management of HCC patients depends on the stage of their tumor. Liver resection remains the first choice for very early-stage HCC, but it is being challenged by local ablative therapy. For early-stage HCC that meet the Milan criteria, liver transplantation still offers a better outcome; however, local ablative therapy can be a substitute when transplantation is not feasible. Local ablation is also used as a bridging therapy toward liver transplantation. HCC recurrence is the main obstacle to successful treatment, and there is currently no effective means of preventing or treating HCC recurrence. Transarterial therapy is considered suitable for intermediate-stage HCC, while sorafenib is recommended for advanced-stage HCC. This stage-based approach to therapy not only provides acceptable outcomes but also improves the quality of life of HCC patients. Because of the complexity of HCC, therapeutic approaches must be adapted according to the characteristics of each individual patient. This review discusses the current standards and trends in the treatment of HCC.
Peter Schemmer, MD
Deptment of General and Transplant Surgery, Ruprecht-Karls-University Im Neuenheimer Feld 110, Heidelberg 69120 (Germany) Tel. +49 0 6221 56 6110, E-Mail [email protected]
Downloaded by: Univ. of California Santa Barbara 198.143.33.33 - 7/30/2015 2:42:37 PM
Copyright © 2012 S. Karger AG, Basel
145
Liver Cancer 2012;1:144–158 DOI: 10.1159/000343828 Published online: November 26, 2012
© 2012 S. Karger AG, Basel www.karger.com/lic
Lin et al.: Systemic Review of HCC Treatment
Introduction Hepatocellular carcinoma (HCC) is the fifth most common form of cancer and the third leading cause of cancer-related death worldwide [1]. The number of cases diagnosed with HCC is expected to increase in Western countries [2]. Therapeutic approaches for the treatment of HCC can be classified into three categories: potentially curative, palliative, and symptomatic. Potentially curative treatments, including liver resection, transplantation, and local ablation, are associated with promising 5-year survival rates of up to 75% [3]. However, because of a shortage of donor livers, advanced tumor stage, or liver dysfunction, less than 20% HCC patients are eligible for such treatments [4, 5]. The majority of HCC patients are subjected to palliative or symptomatic treatment. The 3-year survival rate for palliative treatment is 10–40%, and the duration of survival for patients who receive symptomatic treatment is RFA NA ×
SR>RFA SRRFA
NA NA NA
SR = surgical resection; PTA = percutaneous thermal ablation; D = Diameter of tumor mass; OSR = overall survival rates; ORS = overall recurrence rates; RFSR = recurrence-free survival rates; DFSR = disease-free survival rates; × = no significance.
Early-stage HCC Early-stage HCC is defined according to the Milan criteria as follows: a single tumor nodule ≤5 cm in diameter or ≤3 nodules ≤3 cm in diameter [16]. Approximately 25% of all HCC patients are diagnosed with early-stage HCC [17]. According to the EASL-AASLD guidelines, early-stage HCC is an indication for liver transplantation or RFA [8]. Liver transplantation is the optimal approach, but local ablation can be a substitute when liver transplantation is not feasible. Liver resection should be considered when patients present with a solitary tumor and no portal hypertension [7]. The 4- and 5-year survival rates of patients who meet the Milan criteria and subsequently undergo liver transplantation are 85 and 70%, respectively [16, 18]. Farinati et al. reported that for patients with early-stage HCC, liver transplantation offers the best chances of survival (106 months) compared with surgical resection (52 months), RFA (62 months), percutaneous ethanol injection (PEI, 44 months), and transarterial chemoembolization (TACE, 34 months) [17]. Despite the excellent efficacy of liver transplantation in early-stage HCC treatment, a shortage of donor livers or tumor progression during the waiting period inevitably leads to patients dropping out from the waiting list. The monthly drop-out rate is approximately 4% [18, 19]. Local ablative therapies, primarily RFA, have therefore been investigated as alternative treatments for early-stage HCC that meet the Milan criteria. Although a recent meta-analysis indicated that surgical resection is superior to RFA because it results in longer overall survival, longer recurrence-free survival, and a low rate of local recurrence, the analysis was mainly based on nonrandomized controlled trials and did not include the latest 3-year survival data [20]. The conclusion should therefore be interpreted with caution. To address the efficacy of local ablative therapy in comparison with
Downloaded by: Univ. of California Santa Barbara 198.143.33.33 - 7/30/2015 2:42:37 PM
that RFA was associated with better overall survival compared with surgical resection [15]. Therefore, further research is warranted before local ablation can be recommended as firstline therapy for very early-stage HCC or as a substitute for surgical resection.
148
Liver Cancer 2012;1:144–158 © 2012 S. Karger AG, Basel www.karger.com/lic
DOI: 10.1159/000343828 Published online: November 26, 2012 Lin et al.: Systemic Review of HCC Treatment
Table 3. Summary of transarterial therapies for HCC Author
Year
Doffoël [95]
2008
Llovet [93]
2002
Bruix [97]
1998
Lo [94]
GETCH [135] *P
